OBJECTIVES The trade-off between cost and mortality among stage IV colorectal cancer patients treated with 5FU/leucovorin/oxaliplatin (FOLFOX) or 5FU/leucovorin/irinotecan (FOLFIRI) was examined. Multiple linked data sources were necessary to obtain treatment, cancer stage, cost, and mortality. METHODS Adults with colorectal cancer newly treated with FOLFOX or FOLFIRI were identified from a claims database for services January 1, 2002-December 31, 2005. Privacy board approval for waiver of patient consent was obtained, and cancer stage was abstracted from medical records; death was obtained from the National Death Index. Once matched, 41 FOLFOX and 86 FOLFIRI patients had stage IV cancer and were retained. Costs were analyzed using generalized linear modeling; mortality was modeled using Cox proportional hazards analysis. Both controlled for age, gender, region, comorbidities, and treatment (biologic use, surgery, radiation). Sensitivity analysis of cost was performed to adjust for availability of generic irinotecan in 2008. Relative value of FOLFOX and FOLFIRI was measured by an incremental cost-effectiveness ratio (ICER). Confidence intervals were estimated by bootstrapping with 1000 replications. RESULTS Unadjusted annualized mean cost was $152,213 (95% confidence interval [CI]: $113,547-$190,878) for FOLFOX, $107,994 (95% CI: $92,356-$123,632) for FOLFIRI. Death occurred among 5 (12%) FOLFOX and 42 (53%) FOLFIRI patients. Adjusted analysis found no statistical difference in cost between cohorts. Cox analysis found significant survival advantage for FOLFOX compared to FOLFIRI (Hazard ratio=5.2; 95% CI: 1.7-15.8). Biologic agent use was higher in the FOLFOX cohort and was associated with survival. ICER found one additional life-year saved was $1,236 (95% CI $300-$2350) with FOLFOX compared to FOLFIRI. CONCLUSIONS FOLFOX appears to have favorable cost effectiveness compared to other agents in the treatment of stage IV colorectal cancer, even after factoring in the impact of generic irinotecan.